PMID- 10595525 OWN - NLM STAT- MEDLINE DCOM- 20000107 LR - 20181113 IS - 0961-8368 (Print) IS - 1469-896X (Electronic) IS - 0961-8368 (Linking) VI - 8 IP - 11 DP - 1999 Nov TI - The interaction of neurotrophins with the p75NTR common neurotrophin receptor: a comprehensive molecular modeling study. PG - 2223-33 AB - Neurotrophins are a family of proteins with pleiotropic effects mediated by two distinct receptor types, namely the Trk family, and the common neurotrophin receptor p75NTR. Binding of four mammalian neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), to p75NTR is studied by molecular modeling based on X-ray structures of the neurotrophins and the extracellular domain of p55TNFR, a homologue of p75NTR. The model of neurotrophin/receptor interactions suggests that the receptor binding domains of neurotrophins (loops I and IV) are geometrically and electrostatically complementary to a putative binding site of p75NTR, formed by the second and part of the third cysteine-rich domains. Geometric match of neurotrophin/receptor binding domains in the complexes, as characterized by shape complementarity statistic Sc, is comparable to known protein/protein complexes. All charged residues within the loops I and IV of the neurotrophins, previously determined as being critical for p75NTR binding, directly participate in receptor binding in the framework of the model. Principal residues of the binding site of p75NTR include Asp47, Lys56, Asp75, Asp76, Asp88, and Glu89. The additional involvement of Arg80 and Glu53 is specific for NGF and BDNF, respectively, and Glu73 participates in binding with NT-3 and NT-4/5. Neurotrophins are likely to induce similar, but not identical, conformational changes within the p75NTR binding site. FAU - Shamovsky, I L AU - Shamovsky IL AD - Department of Medicine, Queen's University, Kingston, Ontario, Canada. FAU - Ross, G M AU - Ross GM FAU - Riopelle, R J AU - Riopelle RJ FAU - Weaver, D F AU - Weaver DF LA - eng SI - PDB/1NCA PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Protein Sci JT - Protein science : a publication of the Protein Society JID - 9211750 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Nerve Growth Factors) RN - 0 (Neuroprotective Agents) RN - 0 (Neurotrophin 3) RN - 0 (Receptors, Nerve Growth Factor) RN - 145172-44-7 (neurotrophin 5) RN - P658DCA9XD (neurotrophin 4) SB - IM EIN - Protein Sci 2000 Mar;9(3):623 MH - Amino Acid Sequence MH - Animals MH - Binding Sites MH - Brain-Derived Neurotrophic Factor/chemistry/metabolism MH - Mammals MH - Models, Molecular MH - Molecular Sequence Data MH - Nerve Growth Factors/*chemistry/*metabolism MH - Neuroprotective Agents/chemistry/metabolism MH - Neurotrophin 3/chemistry/metabolism MH - Protein Conformation MH - Protein Structure, Secondary MH - Receptors, Nerve Growth Factor/*chemistry/*metabolism PMC - PMC2144181 EDAT- 1999/12/14 09:00 MHDA- 2000/05/29 09:00 PMCR- 2000/05/01 CRDT- 1999/12/14 09:00 PHST- 1999/12/14 09:00 [pubmed] PHST- 2000/05/29 09:00 [medline] PHST- 1999/12/14 09:00 [entrez] PHST- 2000/05/01 00:00 [pmc-release] AID - 10.1110/ps.8.11.2223 [doi] PST - ppublish SO - Protein Sci. 1999 Nov;8(11):2223-33. doi: 10.1110/ps.8.11.2223.